Ibrutinib Has Time-dependent On- and Off-target Effects on Plasma Biomarkers and Immune Cells in Chronic Lymphocytic Leukemia
Ibrutinib is a covalently binding inhibitor of the B-cell receptor signaling-mediator Bruton’s tyrosine kinase (BTK) with great efficacy in chronic lymphocytic leukemia (CLL). Common side effects like atrial fibrillation (AF), bleeding and infections might be caused by ibrutinib’s inhibition of othe...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-05-01
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| Series: | HemaSphere |
| Online Access: | http://journals.lww.com/10.1097/HS9.0000000000000564 |
| _version_ | 1797285670000001024 |
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| author | Tom A. Mulder Lucía Peña-Pérez Anna Berglöf Stephan Meinke H. Yesid Estupiñán Kia Heimersson Rula Zain Robert Månsson C. I. Edvard Smith Marzia Palma |
| author_facet | Tom A. Mulder Lucía Peña-Pérez Anna Berglöf Stephan Meinke H. Yesid Estupiñán Kia Heimersson Rula Zain Robert Månsson C. I. Edvard Smith Marzia Palma |
| author_sort | Tom A. Mulder |
| collection | DOAJ |
| description | Ibrutinib is a covalently binding inhibitor of the B-cell receptor signaling-mediator Bruton’s tyrosine kinase (BTK) with great efficacy in chronic lymphocytic leukemia (CLL). Common side effects like atrial fibrillation (AF), bleeding and infections might be caused by ibrutinib’s inhibition of other kinases in non-B cells. Five-year follow-up of plasma biomarkers by proximity extension assay and immune cell numbers by flow cytometry during ibrutinib treatment revealed that 86 of the 265 investigated plasma biomarkers significantly changed during treatment, 74 of which decreased. Among the 12 markers that increased, 6 are associated with cardiovascular diseases and therefore potentially involved in ibrutinib-induced AF. Comparison between healthy donors and X-linked agammaglobulinemia (XLA) patients, who have nonfunctional BTK and essentially lack B cells, showed indicative changes in 53 of the 265 biomarkers while none differed significantly. Hence, neither B cells nor BTK-dependent pathways in other cells seem to influence the levels of the studied plasma biomarkers in healthy donors. Regarding immune cells, the absolute number of T cells, including subsets, decreased, paralleling the decreasing tumor burden. T helper 1 (Th1) cell numbers dropped strongly, while Th2 cells remained relatively stable, causing Th2-skewing. Thus, long-term ibrutinib treatment has a profound impact on the plasma proteome and immune cells in patients with CLL. |
| first_indexed | 2024-03-07T18:06:29Z |
| format | Article |
| id | doaj.art-7612645b2ec14e5e86e2bbac72791afb |
| institution | Directory Open Access Journal |
| issn | 2572-9241 |
| language | English |
| last_indexed | 2024-03-07T18:06:29Z |
| publishDate | 2021-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | HemaSphere |
| spelling | doaj.art-7612645b2ec14e5e86e2bbac72791afb2024-03-02T09:12:16ZengWileyHemaSphere2572-92412021-05-0155e56410.1097/HS9.0000000000000564202105000-00008Ibrutinib Has Time-dependent On- and Off-target Effects on Plasma Biomarkers and Immune Cells in Chronic Lymphocytic LeukemiaTom A. Mulder0Lucía Peña-Pérez1Anna Berglöf2Stephan Meinke3H. Yesid Estupiñán4Kia Heimersson5Rula Zain6Robert Månsson7C. I. Edvard Smith8Marzia Palma91 Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden2 Center for Hematology and Regenerative Medicine (HERM), Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden3 Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden4 Department of Medicine Huddinge, Karolinska Institutet, Huddinge, Sweden3 Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden1 Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden3 Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden2 Center for Hematology and Regenerative Medicine (HERM), Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden3 Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden1 Department of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenIbrutinib is a covalently binding inhibitor of the B-cell receptor signaling-mediator Bruton’s tyrosine kinase (BTK) with great efficacy in chronic lymphocytic leukemia (CLL). Common side effects like atrial fibrillation (AF), bleeding and infections might be caused by ibrutinib’s inhibition of other kinases in non-B cells. Five-year follow-up of plasma biomarkers by proximity extension assay and immune cell numbers by flow cytometry during ibrutinib treatment revealed that 86 of the 265 investigated plasma biomarkers significantly changed during treatment, 74 of which decreased. Among the 12 markers that increased, 6 are associated with cardiovascular diseases and therefore potentially involved in ibrutinib-induced AF. Comparison between healthy donors and X-linked agammaglobulinemia (XLA) patients, who have nonfunctional BTK and essentially lack B cells, showed indicative changes in 53 of the 265 biomarkers while none differed significantly. Hence, neither B cells nor BTK-dependent pathways in other cells seem to influence the levels of the studied plasma biomarkers in healthy donors. Regarding immune cells, the absolute number of T cells, including subsets, decreased, paralleling the decreasing tumor burden. T helper 1 (Th1) cell numbers dropped strongly, while Th2 cells remained relatively stable, causing Th2-skewing. Thus, long-term ibrutinib treatment has a profound impact on the plasma proteome and immune cells in patients with CLL.http://journals.lww.com/10.1097/HS9.0000000000000564 |
| spellingShingle | Tom A. Mulder Lucía Peña-Pérez Anna Berglöf Stephan Meinke H. Yesid Estupiñán Kia Heimersson Rula Zain Robert Månsson C. I. Edvard Smith Marzia Palma Ibrutinib Has Time-dependent On- and Off-target Effects on Plasma Biomarkers and Immune Cells in Chronic Lymphocytic Leukemia HemaSphere |
| title | Ibrutinib Has Time-dependent On- and Off-target Effects on Plasma Biomarkers and Immune Cells in Chronic Lymphocytic Leukemia |
| title_full | Ibrutinib Has Time-dependent On- and Off-target Effects on Plasma Biomarkers and Immune Cells in Chronic Lymphocytic Leukemia |
| title_fullStr | Ibrutinib Has Time-dependent On- and Off-target Effects on Plasma Biomarkers and Immune Cells in Chronic Lymphocytic Leukemia |
| title_full_unstemmed | Ibrutinib Has Time-dependent On- and Off-target Effects on Plasma Biomarkers and Immune Cells in Chronic Lymphocytic Leukemia |
| title_short | Ibrutinib Has Time-dependent On- and Off-target Effects on Plasma Biomarkers and Immune Cells in Chronic Lymphocytic Leukemia |
| title_sort | ibrutinib has time dependent on and off target effects on plasma biomarkers and immune cells in chronic lymphocytic leukemia |
| url | http://journals.lww.com/10.1097/HS9.0000000000000564 |
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